Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial or Stage I bladder tumors. Patients with these superficial tumors can often be cured, but those with muscle-invasive or metastatic disease are cured less often and are treated with surgery, irradiation or a combination of modalities that includes systemic therapy. Platinum doublets are widely utilized as first-line treatment in patients with metastatic disease, but minimal options exist for those failing that treatment. No drugs are approved in relapsed/refractory metastatic bladder cancer in the U.S., and the single compound with European approval, Javlor (vinflunine, Pierre Fabre), produced a meager 8.6% response rate and 3.0-month progression-free survival (PFS) in a Phase III trial.1 Thus any serious contender in this setting is a great cause for excitement. With immunotherapy already such a hot topic, atezolizumab (MPDL3280A, Genentech/Roche) is generating considerable enthusiasm.

Atezolizumab is a human monoclonal IgG1 anti-PD-L1 antibody that inhibits the interaction of the PD-1 receptor with the PD-L1 ligand. In June 2011, a “first-in-human” Phase I (NCT01375842, PCD4989g) trial was initiated to assess atezolizumab in patients with locally advanced or metastatic solid or hematologic malignancies. Preliminary results2,3 from this study in the cohort of patients with advanced bladder cancer were so encouraging that it led to the U.S. Food and Drug Administration (FDA) awarding atezolizumab Breakthrough Therapy status as treatment of relapsed/refractory, PD-L1-positive bladder cancer.

In the Sunday Proffered Papers session on genitourinary cancers at the 2015 European Cancer Congress, a packed auditorium eagerly awaited the results of the Phase II IMvigor 210 trial.4 Data was presented from Cohort 2 of the study, which included 311 patients who were previously treated with platinum-based therapy (Cohort 1 includes platinum-ineligible patients). Atezolizumab was administered at 1200 mg IV every three weeks until loss of clinical benefit. The Ventana PD-L1 (SP142) CDx Assay was used to prospectively stratify participants into three PD-L1-based subgroups based on PD-L1 expression levels in immune cells. IC (tumor-infiltrating immune cell) levels were defined as IC0 for patients with PD-L1 expression in less than 1% of cells (33%, n=103), IC1 for patients with PD-L1 expression in more than 1% but less than 5% of cells (35%, n=108), and IC2/3 for patients with PD-L1 expression in 5% or more of cells (32%, n=100).

The overall response rate (ORR) was 9% in patients with IC0 expression level, 10% in IC1, 27% in IC2/3, and 15% across all patients. PFS was 2.1 months in all PD-L1 cohorts, although beyond the median there appeared to be a greater PFS in the IC2/3 cohort (PFS at six months was approximately 35% for IC2/3 and 20% for IC0/1). Median duration of response was not reached in any subgroup (range 0+ to 43 months). Median overall survival was 7.9 months across all patient cohorts; median OS was 6.7 months in IC0/1 patients and was not reached in IC2/3 patients. The safety profile of atezolizumab was similar to what has been observed in other tumor types, with 15% of patients experiencing a Grade 3/4 adverse event; treatment discontinuations were infrequent (3%), but dose modifications due to adverse events were common (27%).

What is most striking about these data is that these are patients who had been heavily treated. Seventy-eight percent had prior systemic regimen treatment for metastatic disease, and 20% had already completed three or more prior lines of therapy. Compared with the 8.6% ORR, 3.0-month PFS, and 6.9-month OS achieved with Javlor in a second-line population, these results are a huge leap.

With such positive Phase II data, Roche intends to seek regulatory approval, with U.S. and European filings expected to occur in early 2016. Guidance from the company is that they will seek approval in the specific subset of patients with PD-L1-positive disease, although the exact definition of “positivity” intended to be sought is unclear. If they follow their lead from non-small cell lung cancer, the regulatory filing may be limited to patients with IC2/3 PD-L1 expression levels. This would be a wise move, considering that the ORR and PFS were strongest in this patient cohort, although arguably the high unmet need in metastatic bladder cancer could justify the use of atezolizumab in a broad patient population.

In the U.S., accelerated approval of atezolizumab in this indication is highly likely given the lack of any approved therapies for relapsed patients and with the drug having already received Breakthrough Therapy designation in this indication. An accelerated approval will give atezolizumab a significant first-to-market advantage over its closest competitor in the immuno-oncology space, Keytruda® (pembrolizumab, Merck & Co.). Keytruda is currently being studied in a Phase III trial for relapsed/refractory metastatic bladder cancer, with a trial design that is nearly identical to that of atezolizumab’s Phase III trial in this setting, although Merck’s trial started a few months ahead of Roche’s, lending importance to an accelerated market launch. For a disease that until recently has had so few treatment options, the results from the 2015 European Cancer Congress are truly “IMvigor-ating”.
References:

Without a doubt, PD-1 and PD-L1 inhibitors have taken the oncology field by storm. With its approval in Japan in July 2014 for unresectable melanoma, Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) was the first PD-1 inhibitor to be approved worldwide and represented the culmination of a longstanding quest to harness the body’s inherent immune system to combat cancer. With the proverbial “cat out of the bag,” the approval also sparked a furious race between Opdivo and its closest competitor, Keytruda® (pembrolizumab, Merck), with the U.S. Food and Drug Administration (FDA) granting Keytruda accelerated approval in relapsed unresectable/advanced melanoma (September 2014) and subsequently approving Opdivo in the same setting (December 2014). All eyes turned to non-small cell lung cancer (NSCLC) in March 2015, when Opdivo became first-in-class in this indication with its approval in second-line squamous histology, and Merck quickly followed suit filing for Keytruda in NSCLC (PDUFA date: October 2, 2015). It seemed initially that these two agents would dominate the field of immuno-oncology; however, agents such as atezolizumab (Roche/Genentech), avelumab (Merck Serono/Pfizer), and durvalumab (MEDI4736, MedImmune/AstraZeneca) have entered the fray, and their entry into late-stage development, particularly in NSCLC, has intensified competition with no signs of abating in the near future. A question (among many) now becomes how will all these agents equilibrate in the market and what factors will guide physicians in their treatment paradigms for NSCLC?

Atezolizumab is Roche/Genentech’s gateway into this hot area. While a slight latecomer, atezolizumab is one of the most advanced immuno-oncology agents, representing a complementary mechanism by being an inhibitor of the PD-L1 ligand. The companies have initiated a broad NSCLC development program for atezolizumab, with three pivotal Phase II trials (FIR, NCT01846416; POPLAR, NCT01903993; and BIRCH, NCT02031458) and one Phase III trial (OAK, NCT02008227) for atezolizumab in second-line NSCLC in an effort to catch up with Opdivo and Keytruda; recently five Phase III trials also were initiated in the first-line setting as well as another Phase III trial in the adjuvant setting. FIR (n=138) and BIRCH (n=667) are single-arm trials of atezolizumab in PD-L1-selected patients in metastatic NSCLC. In both trials, atezolizumab was given at 1200 mg/kg IV every three weeks, and the primary endpoint was objective response rate (ORR). POPLAR (n=287) was a randomized Phase II trial that enrolled all-comers with relapsed metastatic NSCLC, with an accompanied stratification by PD-L1 expression; in this trial, atezolizumab (1200 mg/kg IV every three weeks) was compared with standard-of-care chemotherapy docetaxel (75 mg/m2 IV every three weeks). Roche has consistently guided that these three Phase II trials will form the basis for regulatory applications in the U.S. and Europe.

Interim results for POPLAR and FIR were first reported at the American Society of Clinical Oncology (ASCO) 2015 annual meeting.1,2 Patients in POPLAR who had higher levels of PD-L1 expression in either the tumor (TC1/2/3) or immune cells (IC1/2/3) showed increased overall survival with atezolizumab compared with docetaxel (median not reached versus 9.1 months (HR 0.63, p=0.024)) and the magnitude of overall survival (OS) benefit was greater for patients who more strongly expressed PD-L1 (immunohistochemistry score (IHC) 2/3, HR 0.56; IHC3, HR 0.46); this survival benefit did not significantly differ among patients with TC or IC IHC0. The FIR trial showed that patients expressing a high level of PD-L1 (TC or IC IHC2/3) exhibited an ORR of 29% for first-line patients, 17% for second-line or later patients without brain metastases, and 23% for second-line or later patients with brain metastases. After POPLAR and FIR reported data at ASCO 2015, the last of the Phase II trials, BIRCH, was highly anticipated. In August 2015, Roche announced that BIRCH had met its primary endpoint and induced tumor shrinkage in patients who expressed PD-L1, and that PD-L1 expression correlated with response; the results were presented Sunday at the 2015 European Cancer Congress in Vienna.3

The BIRCH trial evaluated atezolizumab in patients with locally advanced or metastatic NSCLC who expressed high levels of PD-L1 on either TC or IC, as determined by the VENTANA SP142 IHC assay. TC2/3 or IC2/3 was equal to or greater than 5% of PD-L1-positive TCs or ICs, while TC3 or IC3 was equal to or greater than 50% TCs or 10% ICs expressing PD-L1. Patients were stratified into three cohorts: Cohort 1 had received no prior chemotherapy (n=142), Cohort 2 had received one prior platinum chemotherapy (n=271), and Cohort 3 had received at least two prior chemotherapies including one platinum (n=254). Patients were treated until progressive disease or until loss of clinical benefit. The ORR in all three patient cohorts correlated with level of PD-L1 expression: ORR for IHC2/3 versus IHC3 was 19% versus 26% in Cohort 1; 17% versus 24% in Cohort 2; and 17% versus 27% in Cohort 3. Median PFS was 5.5 months, 2.8 months and 2.8 in Cohorts 1, 2, and 3 in patients with TC-IC2/3, while a similar trend was seen in patients with TC-IC3 (Cohort 1 5.5 months, Cohort 2 4.1 months, Cohort 3 4.2 months). OS data is not yet mature; however, six-month OS rates in Cohorts 1, 2, and 3 were 82%, 76% and 71%, respectively, in IHC2/3 patients and 79%, 80%, and 75% in Cohorts 1-3 in the IHC3 population. Adverse events seen with atezolizumab were similar to those seen in other studies, with the most common Grade 3/4 adverse events being rash, pneumonitis, elevated liver transaminases and colitis, all which had a frequency less than 2% each.

Roche has guided that it plans to file for regulatory approval in the U.S. and EU in 2016; in light of the Breakthrough Status granted by the FDA, combined results from FIR, POPLAR, and BIRCH should support an accelerated approval of atezolizumab in patients with PD-L1-positive, relapsed metastatic NSCLC. A question that stands out is how Roche will differentiate atezolizumab from its competitors and how will physicians adopt atezolizumab in their clinical practice. In terms of entry into market, Opdivo is ahead of atezolizumab, allowing Opdivo to establish itself in clinical practice. While cross-trial comparisons should always be made with caution, the survival curves in Opdivo’s CheckMate-017 and CheckMate-057 trials in second-line NSCLC and atezolizumab’s POPLAR trial in second-line NSCLC indicate very similar levels of efficacy between Opdivo and atezolizumab, so similar that the BIRCH trial discussant, Dr. Luiz Paz-Ares, stated that the trials “confirmed each other.” Given the similar level of benefit, it is unlikely atezolizumab will compete with Opdivo based on efficacy alone. Additionally, Keytruda is expected to receive FDA approval in relapsed NSCLC very shortly, thus putting atezolizumab third to market in the U.S.

One point of differentiation is in patient selection. The data showing increased response in patients with higher PD-L1 supports a regulatory filing in PD-L1-positive patients for atezolizumab, which is also supported by its FDA Breakthrough Therapy designation in this patient type; Opdivo is unlikely to have such a biomarker-restricted label, and whether or not Keytruda’s label will include a biomarker restriction is an area of hot debate. If atezolizumab becomes the first of these drugs to be approved with a PD-L1-positive biomarker limitation in its label, this could prove advantageous. Physicians may shift their preference toward atezolizumab if the efficacy is more pronounced in this patient population or if payers strictly enforce PD-L1 biomarker testing and subsequently choice of PD-1 or PD-L1 inhibitor. The loss of a fraction of patients who are PD-L1-negative if a restricted label is granted may be counterbalanced by the gain of greater market share among patients who are PD-L1-positive than might have been obtained by competing against two other drugs in an all-comers population.

Many questions remain (largely around implementation of the PD-L1 diagnostic), and physicians will soon find themselves with many arguably similar therapeutic choices for their relapsed NSCLC patients. Until more definitive data becomes available to better guide immuno-oncology treatment decisions, physicians may be left analyzing individual “trees” before the forest that is the clinical paradigm for immuno-oncology products can be fully understood.

Sutent® (sunitinib, Pfizer) and Votrient® (pazopanib, Novartis) are currently considered the standards of care for first-line therapy in renal cell carcinoma (RCC). However, neither drug (nor any other agents currently approved) has been able to show an overall survival (OS) benefit in clinical trials; they were approved by regulatory agencies based on a significant improvement in progression-free survival (PFS). Since 2005, seven agents have been approved, including Sutent and Votrient, on the basis of PFS alone.

Moreover, the presence of two established agents with strong utilization in the first-line setting contributes to the need for agents that can be utilized following relapse. Two agents are currently approved for use in this setting – Afinitor® (everolimus, Novartis), based on significant improvements in PFS compared with placebo, and Inlyta® (axitinib, Pfizer), based on significant improvement in PFS compared with Nexavar® (sorafenib, Bayer/Amgen). Given the lack of proven OS benefits for any of these agents, an opportunity exists for an agent that can establish a significant benefit for this endpoint. It is in this framework that two trials presented in the Presidential Symposium Saturday at the 2015 European Cancer Congress finally show the possibility of improving OS. The trials were CheckMate-025, which evaluated Opdivo® (nivolumab, Bristol-Myers Squibb/Ono), and METEOR, which evaluated Cometriq® (cabozantinib, Exelixis).

CheckMate-025 was the first of these two studies to be presented.1 This trial compared Opdivo (3 mg/kg every two weeks) to daily oral Afinitor (10 mg) in 821 advanced or metastatic clear-cell RCC patients who had been treated with one or two prior anti-angiogenic therapies. The trial was stopped early by the data-monitoring committee in July 2015 as the statistical boundary for declaring OS superiority of Opdivo had been reached. Opdivo reduced the risk of death by 27% (median OS: 25.0 months versus 19.6 months, HR 0.73, p=0.0018). Most subgroups favored Opdivo, although the arms for elderly patients (75 years or older), patients with favorable MSKCC risk status, or patients who had received two prior therapies (confidence interval overlapped the mark for non-significance)showed no apparent difference ,. Tumor PD-L1 positivity, defined as PD-L1 membrane expression in 1% or more of cells stained using the Dako immunohistochemical kit, was not predictive of activity. The objective response rate was improved (25% versus 5%, OR 5.98, p<0.0001), but the duration of response (12.0 months in both arms) and PFS (4.6 months versus 4.4 months, HR 0.88, p=0.1135) were not improved.

Opdivo was better tolerated than Afinitor, with fewer treatment-related Grade 3/4 adverse events than Afinitor (19% versus 37%). The more common toxicities of any grade for Opdivo included fatigue (33%), nausea (14%), pruritus (14%), diarrhea (12%), and decreased appetite (12%). The improved efficacy and tolerability were reflected in an improved score in quality of life as measured by the FKSI-DRS questionnaire (p<0.05).

METEOR was presented next in the session.2 METEOR compared oral daily Cometriq (60 mg) with oral daily Afinitor (10 mg) in 658 advanced clear-cell RCC patients who have progressed on a prior VEGFR tyrosine kinase inhibitor (TKI) within six months of enrollment. Despite that inclusion criterion, there was no limit to the number of prior therapies as 29% of patients on the Cometriq arm received two or more prior VEGFR TKI treatments. Other therapies were also allowed but had been less frequently offered to the enrolled patients.

METEOR achieved its primary endpoint, which was PFS, with a 3.6-month improvement (HR 0.58, p<0.001). Subgroup analysis suggested that Cometriq improved PFS in most patients, but PFS may not have been significantly improved in those with two or more prior therapies or a poor MSKCC risk status. The response rate was also improved (21% versus 5%, p<0.001). OS was not yet reached but trended to significance with Cometriq (HR 0.67, p=0.005). The medians could not be estimated due to frequent early censoring, and the interim boundary for significance was set at p=0.00019). As the Kaplan-Meier curves were clearly separated from one another and these data are immature, it is expected that a significant OS benefit ultimately will be reached.

Cometriq had some toxicities but was generally well-tolerated. Grade 3 or 4 adverse events were higher in the Cometriq arm (68% versus 58%) and were reflected in a higher percentage of dose reductions (60% versus 25%). Select Grade 3/4 toxicities of note, compared with Afinitor, included hypertension (15% versus 3%), diarrhea (11% versus 2%) and palmar-plantar erythrodysesthesia (8% versus less than 1%); anemia (5% versus 16%) and hyperglycemia (less than 1% versus 5%) were improved in the Cometriq arm.

If METEOR does not reach its threshold for statistical significance, the decision for physicians will be easy: Choose Opdivo for its improvement in OS. If the OS benefit in METEOR becomes statistically significant (and the Kaplan-Meier curves strongly suggest that it will do so), then physicians will have a more difficult decision to make. The high excitement level for immuno-oncology agents in general, coupled with its seemingly more favorable tolerability, may lead physicians to opt first for Opdivo. On the other hand, Cometriq does have its own advantages, perhaps most notably the ability to delay progression (by 3.6 months at the median in the METEOR trial).

CheckMate 025

METEOR

Opdivo

Afinitor

HR

Cometriq

Afinitor

HR

mOS, mos.

25.0

19.6

0.73

Median not available

0.67

mPFS, mos.

4.6

4.4

0.88

7.4

3.8

0.58

Total Grade 3/4 AEs (%)

19

37

68

58

Making two assumptions – that the METEOR trial ultimately shows a significant OS benefit and that regulatory agencies will approve the two drugs within a few months of each other – these two agents will have a hefty competition for market share in second-line RCC. The toxicity profile for Opdivo may favor its use in many patients, although Cometriq might end up being the agent of choice for select patients, such as those who are older than 75 years of age, where Opdivo appears less effective. In a way, this is a good problem, at least for oncologists and their patients. It’s always better to question which of several good agents to choose from rather than having few options or none at all.

The role of Programmed Death-1 (PD-1) pathway in suppression of antitumor immunity has become one of the hottest topics in oncology over the past couple of years. PD-1 is a key immune checkpoint receptor expressed on activated T-cells, and binding of PD-1 to its ligand (PD-L1) results in the suppression of the immune response. While the PD-1 pathway normally plays a protective role by attenuating immune-mediated destruction of healthy tissue, the pathway can be exploited by cancer cells to protect themselves from the attack by tumor-specific T-cells. A number of immune checkpoint inhibitors are in late-stage clinical development; these agents work by blocking the interaction between PD-1 and PD-L1, thereby activating the immune system against cancer cells.

PD-1 Pathway Inhibitors in Phase III Development

Drug

Manufacturer

Antibody

Target

Development Stage

Ongoing pivotal trials

Keytruda

Merck

Humanized IgG4

PD-1

Approved in Yervoy-treated melanoma (U.S.); Phase III

Melanoma, NSCLC, Head and Neck

Opdivo

BMS

Human IgG4

PD-1

Filed in Yervoy-treated melanoma (US/EU)

Filed in squamous 3rd line NSCLC (US/EU); Phase III

Melanoma, NSCLC, RCC, Head and Neck

MPDL3280A

Roche

Human IgG1

PD-L1

Phase III

Bladder, NSCLC

MEDI-4736

AstraZeneca

Human IgG1

PD-L1

Phase III

NSCLC

For these novel immune checkpoint inhibitors, the fight to capture the lead in high-profile tumor types such as melanoma and non-small cell lung cancer (NSCLC) is becoming increasingly fierce. But their clinical development does not end there and, in fact, continues to expand into other indications, such as renal cell carcinoma (RCC), urothelial cancer, head and neck cancer, gastrointestinal cancer and hematological malignancies. Data continued to report promising activity across different tumor types at the annual 2014 European Society for Medical Oncology (ESMO), as summarized below.

Past oncology meetings have highlighted the promise of Opdivo™ (nivolumab, Bristol-Myers Squibb) in melanoma. Opdivo demonstrated impressive early clinical data that suggested improved overall response rate (ORR) with fewer toxicities when compared with historical data for Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 immune checkpoint inhibitor. At ASCO 2014, another anti-PD-1 monoclonal antibody, Keytruda® (pembrolizumab, Merck), took center stage with impressive Phase II data that ultimately led to its approval in the U.S. in September 2014 as therapy for Yervoy-treated melanoma patients.

Recognizing the urgency of getting to market as soon as possible, BMS submitted U.S./EU regulatory applications for Opdivo for Yervoy-treated melanoma, with expected U.S. approval in March 2015. Once Opdivo becomes approved, physicians will look to efficacy and safety data to drive their decision when choosing between the two agents. At ESMO, highly anticipated data from a randomized Phase III study (Opdivo versus chemotherapy of choice) were presented for 405 previously treated (including Yervoy) unresectable Stage III/IV melanoma patients.

The ORR was 32% for Opdivo versus 11% for chemotherapy, with benefit observed across all subgroups, including PD-L1 negative patients. Grade 3/4 toxicities were reported in 9% of patients in the Opdivo arm versus 31% in the chemotherapy arm, with no new safety signals reported. Unfortunately, the progression-free survival (PFS) and overall survival (OS) data were not yet available at the time of analysis, but duration of response among responding patients suggests prolonged benefit (3.6 months in the chemotherapy arm versus median not reached in the Opdivo arm but with 95% of responders still benefiting at six months). So how does Opdivo compare to Keytruda in this patient population? As shown below, the activity appears very similar between the drugs, and no dramatic differences exist in their safety profiles.

Efficacy in Previously-Treated Metastatic Melanoma

Drug

ORR

CR

mPFS

Opdivo (n=120)

32%

3%

ND

Chemotherapy (47)

11%

0%

ND

Keytruda (n=197)1

28%

2%

5.6 mos

1Ribas, Abstract LBA9000, ASCO 2014

While response rate is a valid and informative endpoint about the drug’s efficacy, PFS and OS data ultimately might help decide which of the two will become the winner. This is especially important for Opdivo’s trial, in which OS was the co-primary endpoint. Will the improved response rates translate into a statistically significant OS benefit that supports the regulatory applications? The expected answer is yes, although due to immature data we now continue to wait with bated breath for this data. While Keytruda already demonstrated that PD-1 inhibitor works in Yervoy-treated melanoma patients, the results from the Opdivo trial were significant in that it presented, for the first time, data from a randomized Phase III study. Commercially, Keytruda will have a six-month time-to-market advantage over Opdivo and will likely amass a strong foothold in the Yervoy-pretreated setting by the time Opdivo launches. Will having overall survival data from a randomized study (assuming it is available by the time of launch) sway physicians to forgo Keytruda in favor of Opdivo, or will physicians interpret a positive survival benefit for Opdivo to be a surrogate for similar expectations with Keytruda?

The study evaluated whether the expression of PD-L1 biomarker correlates with outcomes. Strong PD-L1 expression was defined as 50% or higher membrane staining in tumor cells and weak expression as 1-49%. The ORR correlated with the level of PD-L1 expression (37% for strong positive, 17% for weak positive and 10% for negative). PFS was also longer for patients with strong versus weak PD-L1 expression (HR 0.52), as was OS (HR 0.59). While the efficacy certainly appears better for PD-L1 positive patients, it is not a black-and-white scenario, and many unresolved issues remain. Namely, differences exist in how the PD-L1 biomarker is measured in the different assays that the various manufactures are developing (what antibody is used), how tissue is collected (old, frozen tissue versus fresh biopsy), where it is measured (tumor cells versus tumor-infiltrating immune cells) and which cutoff threshold is used (1% versus 5% versus others). More importantly, a subset of PD-L1 negative patients still derive a benefit from these inhibitors, yet many of the pivotal trials in NSCLC are conducted in PD-L1 positive tumors. How will that affect the real-world patients, and will the biomarker-negative patients be denied treatment if the drugs receive PD-L1 positive labels (especially outside of the U.S., where payers tend to impose stricter rules)? Keytruda is exclusively targeting PD-L1 positive patients in its pivotal NSCLC trials, while BMS chose to target both PD-L1 positive patients as well as all-comers (including squamous and non-squamous histologies). If those trials are positive, perhaps the inclusion of these patients will enable BMS to have a competitive marketing edge over Keytruda.

While the data presented for Keytruda was certainly very encouraging, how does it compare with the other key competitors that are also vying to win the NSCLC space? At a first glance, it appears that the agents have similar levels of activity in terms of response rates and survival. But the data are still premature, and the efficacy and safety could start differentiating as more patients are enrolled and longer follow-up becomes available. For now, there is no clear winner in NSCLC, and it has yet to be determined whether targeting the receptor versus ligand may prove to be a more efficacious or safer strategy.

Drug

NSCLC ORR

(all)

NSCLC ORR

(1st line)

NSCLC ORR (pretreated)

mPFS

mOS

MPDL3280A1

23% (n=53)

ND

23% (n=53)

ND

ND

MEDI-47362

16% (n=58)

ND

16% (n=58)

ND

ND

Opdivo3

17% (n=129)

30% (n=20)

17% (n=129)

2.3 mos

9.9 mos

Keytruda4

21% (n=236)

26% (n=42)

20% (n=194)

2.5 mos

8.2 mos

1Soria, 1322P, ESMO 2014

2Brahmer, Abstract 8021, ASCO 2014

3Gettinger, Abstract 8024, ASCO 2014

4Garon, LBA43, ESMO 2014

In terms of approval timelines in NSCLC, BMS has an advantage over the other agents as it already submitted a regulatory application in the EU and a rolling submission in the U.S. for Opdivo as a third-line therapy in squamous NSCLC. The submissions were based on data from a Phase II study, and the drug could be approved in both regions next year.

Keytruda shows promising activity in gastric and urothelial cancers

Like BMS, Merck is also pursuing an aggressive development strategy for Keytruda that spans multiple tumor types. Promising preliminary results were reported at ESMO for the gastric cancer (Muro, Abstract LBA15) and urothelial cancer (Plimack, Abstract LBA23) cohorts from the KEYNOTE-012 Phase Ib study. In the gastric cancer presentation, 162 patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) were screened to identify 65 (40%) patients with PD-L1 positive tumors, who were then treated with 10 mg/kg Keytruda every two weeks. Keytruda showed an acceptable safety profile in 39 evaluable patients, although there was one incidence each of Grade 4 pneumonitis and Grade 5 (fatal) hypoxia. Keytruda achieved 30.8% ORR (no complete responses) and reduction in tumor size in 41% of patients. Efficacy was similar in Asian and non-Asian patients, and responses were durable. Based on these results, initiation of a Phase II trial in advanced gastric cancer is expected in in the first quarter of 2015.

In the urothelial cancer cohort, 95 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder or urethra were screened to identify 61 (64.2%) patients with PD-L1 positive tumors. Thirty-three patients with PD-L1 positive tumors were treated with 10 mg/kg Keytruda every two weeks. Grade 3 or higher adverse events were observed in four patients and included AST increase, dehydration, neuromyopathy, macropapular rash, pruritic rash, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy (n=1 for each, some patients had multiple Grade ≥3 adverse events). The ORR was 24.1% (including three complete responses), and a reduction in tumor size was observed in 64% of patients. Six of the seven responses were ongoing, and median duration of response was not reached at a median follow-up of 11 months. These promising results served as the impetus for the Phase III KEYNOTE-045 trial scheduled to begin by the end of 2014.

MPDL3280A shows promising activity in monotherapy activity in bladder, and activity in RCC in combination with Avastin, but will it succeed in CRC?

Roche/Genentech was awarded breakthrough therapy status for its MPDL3280A in urothelial bladder cancer (UBC) in May 2014. Unlike Opdivo and Keytruda, this antibody targets the ligand (PD-L1) rather than receptor, but it is too early to tell whether this strategy will translate into better efficacy and/or a better safety profile. Perhaps recognizing the increasing crowdedness and being too late to the melanoma market, Roche’s clinical development strategy has focused on other tumor types, including NSCLC and RCC as well as the less commercially attractive (in the eyes of big pharma) urothelial/bladder space. Its first potential approved indication is likely to be bladder, in which they could file for an accelerated approval based on data from the ongoing Phase II study, thus potentially beating Keytruda to the market in the urothelial space. It would certainly give physicians the chance to become familiar with the agent in the real-world setting so that by the time the agent is approved (if successful) in larger indications, it may ease the adoption process by clinicians; being approved on the market could also aid in off-label utilization following positive Phase III data in other tumor types, bypassing a delay for supplemental regulatory approval. In terms of its activity in metastatic RCC as monotherapy, data were presented from a Phase I expansion cohort that included 69 patients (McDermott, Abstract 809O). MPDL3280A was very well-tolerated in these patients with Grade 3 or higher fatigue reported in two patients; all other adverse events were Grade 1/2. In 62 evaluable patients, the ORR was 20% in patients with PD-L1 expression of IHC1+/2+/3+ (including one complete and six partial responses) and 10% in patients who were PD-L1 negative (IHC0).

While the inhibitors have been primarily tested as monotherapy, the next wave of trials will examine their efficacy in combination with other regimens, such as chemotherapy, targeted therapy and other immune modulators. Not surprisingly, Roche has already begun the clinical development of MPDL3280A in combination with Avastin® (bevacizumab) and reported preliminary data from a Phase Ib study (Lieu, Abstract 1049O). The study had two arms: Arm A (n=35) evaluated MPDL3280A IV every three weeks plus Avastin 15mg/kg IV every three weeks; Arm B (n=36) evaluated MPDL3280A IV every two weeks plus Avastin 10mg/kg every two weeks and FOLFOX. Dose expansion cohorts in Arm A included patients with colorectal cancer (CRC) and other solid tumors, including breast, melanoma, NSCLC and RCC; Arm B included oxaliplatin-naïve CRC (with or without liver lesions) as well as other solid tumors, including RCC and breast cancer. In Arm A, the combination with Avastin achieved 40% ORR in the first-line RCC cohort (n=10) and 8% ORR in CRC patients. In Arm B, the combination with Avastin plus chemotherapy achieved 36% ORR in CRC.

Avastin plus chemotherapy has been a blockbuster regimen in the treatment of CRC, so it is not surprising that Roche is pushing the combination with its PD-L1 inhibitor. Notably, initial data from Opdivo’s Phase I trial did not show activity in CRC (or prostate cancer), so CRC has not been on the forefront of pivotal studies for other PD-1 inhibitors. While the 36% ORR is certainly encouraging, one must question how much of it was contributed by Avastin plus chemotherapy alone. The response rate appears similar to that observed in pivotal trials for Avastin plus chemotherapy, so the early readout seemed perhaps a bit underwhelming.

But the response rate may not be the best endpoint to evaluate the efficacy of the combination regimen as immunotherapy does not always follow the standard response kinetics and can be associated with delayed responses. So it is still possible that longer follow-up might show improved survival, but will it produce truly stellar results as we have seen so far for the combination of two checkpoint inhibitors in melanoma (Sznol, Abstract LBA9003, ASCO 2014)? In the absence of randomized data, it is difficult to say whether this combination will pan out in CRC. The data in RCC, on the other hand, appear much more promising for the Avastin combination, although the number of patients was small. Avastin has shown efficacy as monotherapy in frontline RCC by achieving approximately 13% ORR, so the reported 40% ORR when combined with PD-L1 inhibitor provides encouraging evidence that the improved efficacy is driven by the addition of MPDL3280A. The activity of the combination regimen certainly appears higher compared to MPDL3280A alone, as discussed above, and might be the strategy going forward, although no such plans have been announced yet. It certainly would help Avastin garner greater utilization in RCC, where it is approved but not a key competitor. However, MPDL3280A plus Avastin will find itself competing with Opdivo, which is currently being studied in combination with Yervoy as first-line therapy for RCC in a head-to-head trial versus Sutent® (sunitinib, Pfizer).

The amount of data presented at ESMO on the role of immune checkpoint inhibitors was impressive and quite overwhelming. It has become very clear that PD-1 targeted drugs are considered a major breakthrough in oncology with the promise to make a meaningful impact in the lives of patients with various malignancies. To date, data has focused on their activity in solid tumors, but we expect to see the first sets of data for these agents in hemtatologic malignancies at the upcoming American Society of Hematology (ASH) conference. It is the beginning of exciting times in oncology and we can all sit back and enjoy the fight for the PD-1 space spanning multiple tumors.